Complement protein C3 is a therapeutic target for the treatment of a variety of human diseases, disorders, and conditions. Proteolytic cleavage of C3 by specific C3 convertases plays a major role in complement pathway activation. C3 convertases generate forms of C3b, which, in turn, are potential components of new C3 convertase molecules, thereby stimulating and amplifying the complement cascade.
Unwanted activation of the alternative complement pathway has been suggested as a possible cause of nephropathies such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G), a form of membranoproliferative glomerulonephritis that encompass dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). As they progress, these diseases harm and degrade kidney function. Since the glomerular membrane lacks endogenous complement regulatory membrane proteins that could otherwise inhibit complement pathway activation, continuous and unregulated cleavage of C3 occurs at this site in individuals with complement-related nephropathies, resulting in deposition of complement activation products, C3 convertase-mediated damage of the glomerular basement membranes, damage to epithelial tubules and endothelial cells, membrane thickening due to deposition of extracellular matrix, deposition of components of the complement system (e.g., C3 cleavage products) and, ultimately, defective filtration (proteinuria) and kidney failure.
Evaluation of the pharmacokinetics (PK) and pharmacodynamics (PD) of candidate therapeutic molecules that specifically target human C3 proteins for the treatment of complement-related nephropathies are routinely performed in non-human animals, e.g., rodents, e.g., mice or rats. However, the PD of such therapeutic molecules cannot properly be determined in certain non-human animals because these therapeutic molecules do not target the endogenous C3 proteins or genes.
Accordingly, there is a need for non-human animals, e.g., rodents, e.g., murine animals, e.g., mice or rats, in which the C3 genes of the non-human animal are humanized in whole or in part or replaced (e.g., at the endogenous non-human loci) with human C3 genes comprising sequences encoding human or humanized C3 proteins. Such animals could potentially serve as ideal models for assessing the efficacy of candidate therapeutics for the treatment of complement-related nephropathies, such as those associated with excessive activation of the alternative complement pathway due to pathological levels of C3 deposition in the kidney, particularly if the engineered non-human animals exhibit symptoms of these conditions corresponding to those observed in human disease.
Throughout this specification, various patents, patent applications and other types of publications (e.g., journal articles, electronic database entries, etc.) are referenced. The disclosure of all patents, patent applications, and other publications cited herein are hereby incorporated by reference in their entirety for all purposes.